Method for preparing 2-acetyl-γ-butyrolactone

ABSTRACT

A method is provided for the preparation of 2-acetyl-γ-butyrolactone by condensing γ-butyrolactone with an acetic acid ester in the presence of a strongly basic condensation agent, followed by protonation of the initially formed enolate, wherein the γ-butyrolactone, the acetic acid ester and the condensation agent are fed continuously into the reaction zone in a ratio of from 1.0 to 6.0 parts by mols of acetic acid ester and from 0.9 to 1.6 parts by mols of the strongly basic substance per part by mols of γ-butyrolactone, and wherein the reaction mixture formed by condensation is withdrawn from the reaction zone, either batchwise or continuously, and protonated.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for preparing2-acetyl-γ-butyrolactone by continuous reaction of γ-butyrolactone andan acetic acid ester in a condensation reaction in the presence of astrongly basic condensation agent.

2. Discussion of the Background

2-Acetyl-γ-butyrolactone is a valuable intermediate for the preparationof active ingredients for drugs, pesticides and various heterocycliccompounds.

The conventional preparation of 2-acetyl-γ-butyrolactone by condensationreaction of butyrolactone with acetic acid esters, followed byprotonation (or neutralization) of the initially produced enolate isknown and is represented by the following general reaction: ##STR1##

In the formulae R¹ and R² are identical or different lower alkylradicals, M is an alkali metal ion or a quaternary ammonium ion, and Xrepresents a radical of an acid and X an anion of the acid.

Acetylation of γ-butyrolactone with acetic acid esters in the presenceof strongly basic substances (such as sodium, potassium, sodium amide,sodium hydride or alkali metal alcoholates) has been described by F.Korte in Angewandte Chemie, 71, 23, 709-752 (1959). According tolaid-open Japanese patent application 45/009 538, butyl acetate is usedspecifically as the acetic acid ester and sodium butoxide as the alkalimetal alcoholate.

In contrast, M. A. Lipkin et al., Khim.-Farm. Zh., 22(12) 1465-1469,recommend ethyl acetate and sodium methoxide for their batchwise methodand report yields of 75% of the theoretical yields. According tolaid-open Japanese patent application 58,099,473, the yield resultingfrom the use of these substances can be improved to 80-85% of thetheoretical yield by also employing additional, highly polar solventssuch as dimethylformamide and/or dimethylacetamide. In otherpublications, such as Polish patent 157,263 or laid-open Japanese patentapplication 58/162,585, acyl halides, rather than acetic acid esters,are recommended as acylation agents. In these cases, however, the yieldsare low and chlorinated organic by-products are formed, which can beremoved by distillation but only with considerable difficulty. Moreover,the costs for the materials used are higher than with the methodsemploying the inexpensive acetic acid esters.

SUMMARY OF THE PRESENT INVENTION

Accordingly, one object of the present invention is to provide a processfor the preparation of 2-acetyl-γ-butyrolactone that provides highpurity product in a high yield and requires only a single distillationfor purification of the product.

A further object of the present invention is to provide a process forthe preparation of 2-acetyl-γ-butyrolactone that provides minimized sidereactions and improved reaction selectivity with respect toγ-butyrolactone.

A further object of the present invention is to provide a process forthe production of 2-acetyl-γ-butyrolactone that requires significantlyless energy to perform and is simpler to control than conventionalmethods.

These and other objects of the present invention have been satisfied bythe discovery of a process for the preparation of2-acetyl-γ-butyrolactone by continuous reaction of γ-butyrolactone andan acetic acid ester in the presence of a strongly basic condensationagent, followed by protonation of the initially formed enolate, whereinthe γ-butyrolactone, the acetic acid ester and the strongly basicsubstance, in a ratio of from 1.0 to 6.0 parts by mols of acetic acidester and from 0.9 to 1.6 parts by mols of the strongly basiccondensation agent per part by mols of γ-butyrolactone, are fedcontinuously into a reaction zone in which the condensation reactiontakes place and from which the reaction mixture is drawn off, batchwiseor continuously, and is protonated.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to a method for the preparation of2-acetyl-γ-butyrolactone from γ-butyrolactone and an acetic acid esterby reacting these two compounds in the presence of a strongly basiccondensation agent, followed by protonation of the initially formedenolate, wherein the reactants are fed continuously into a reaction zonein which the condensation reaction takes place and from which thereaction mixture is drawn off, either batchwise or continuously. Thereactants are used in a ratio of from 1.0 to 6.0 parts by mols of aceticacid ester and from 0.9 to 1.6 parts by mols of the strongly basiccondensation agent per part by mols of γ-butyrolactone. After thereaction mixture is withdrawn from the reaction zone, it is protonatedto provide the final product.

The method according to the present invention provides a number ofsurprising advantages. The 2-acetyl-γ-butyrolactone is obtained, after asingle distillation, in >99% purity and in excellent yields of more than90%, based on γ-butyrolactone used. Thus, the γ-butyrolactone is reactedwith a high degree of selectivity. Side reactions and/or secondaryreactions, which reduce the selectivity and the yield of2-acetyl-γ-butyrolactone, are largely suppressed. Thus hydroxy- oralkoxybutyric acid derivatives, for example, which not only reduce theyield but cannot easily be separated by distillation from2-acetyl-γ-butyrolactone, are produced in considerably smaller amountsthan with the prior art methods.

The selectivity and the yield are, surprisingly, even better than theyare with concomitant use of additional polar solvents according to theabovementioned laid-open Japanese patent application 58/099,473. The useof an additional polar solvent also brings a disadvantage in a reducedspace-time yield and in additional distillation effort needed. This isespecially true if alkali metal alcoholates are used as the stronglybasic condensation agent, since during reaction they will produceadditional alcohol. The concomitant use of nonpolar, inert solvents suchas toluene, on the other hand, is possible without significantlyimpairing the yield obtained.

The present method consumes less energy and is simpler to control thanthe batchwise prior art methods. The present inventors have found thatbatchwise mixing of γ-butyrolactone with an alcoholate releases aconsiderable amount of heat. When sodium methoxide was used as thestrongly basic condensation agent, the amount of heat generated wasmeasured at -55 kJ per mol of γ-butyrolactone. An attempt to performthis batchwise process on an industrial scale would be too demanding interms of control and safety, due to the switch from cooling, required atthe outset, to heating, required subsequently. Further, a great deal ofenergy would be wasted in the switch from cooling to heating. Thepresent method fully uses the abovementioned heat released and can bemanaged, in a steady state, simply and reliably in terms of control andsafety, since the system does not give off any heat, and only minorreadjustment is required.

Finally, the yield of 2-acetyl-γ-butyrolactone is further improved if,during the protonation step using an acid, a temperature of from -5° to+50° C. (preferably at 10° C. to 30° C.) and, in particular, a specificpH, viz. from 4 to 7 (preferably 5 to 6.5) are maintained. If thereaction mixture is introduced into the acid, or the acid is added tothe reaction mixture without any special precautions, the stronglyacidic environment to which the 2-acetyl-γ-butyrolactone is exposed,prior to the point of neutrality being reached, results in hydrolysisreactions with concomitant considerable losses in yield.

Suitable acetic acid esters for use in the present method include aceticacid esters with monohydric alcohols, such as methanol, ethanol, 1- and2-propanol, 1- and 2-butanol, 2-methyl-1-propanol, 1-hexanol,2-ethyl-1-hexanol, benzyl alcohol and β-phenylethylalcohol.

Low boiling point alcohols are preferred since their removal is easierduring distillation.

Esters from alkanols having from 1 to 4 carbon atoms are more preferredwith particular preference given to methyl acetate. Since the alcoholradical of the acetic acid ester is eliminated as alcohol in the courseof the condensation reaction, a mixture of acetic acid esters can beused with little or no effect on the resulting product.

Any conventional strongly basic condensation agent can be used in thepresent invention.

Among the strongly basic condensation agents (hereafter "condensationagent"), the alkali metal alcoholates are preferred, with the lithium,sodium and potassium alcoholates being most preferred. These metalalcoholates are preferably derived from alkanols having from 1 to 4carbon atoms. Particular preference is given to sodium ethoxide and, inparticular, sodium methoxide. Other suitable condensation agents are thealkali metals, alkali metal hydrides and amides. Instead of a singlecondensation agent, it is also possible to use a mixture of two or morecondensation agents. The condensation agent may be fed in a finelydisperse form, e.g. as commercially available sodium methoxide powder,by means of conventional feeders such as proportioning screws etc.Alternatively, the finely disperse, condensation agent can be suspendedin an aliquot of the acetic acid ester or in an inert nonpolar organicsolvent, such as toluene. Stirred suspensions with a solids content offrom 30 to 60 wt. % can often be proportioned more readily and moreaccurately than the solids on their own.

Preferably, the γ-butyrolactone, the acetic acid ester and thecondensation agent are used in amounts of from 1.0 to 5.0, preferablyfrom 1.05 to 2.5 parts by mols of acetic acid ester and from 1.0 to 1.5,preferably from 1.05 to 1.4 parts by mols of the condensation agent perpart by mols of γ-butyrolactone. The proportion of acetic acid ester canbe increased beyond the stated amounts, although the space-time yield isreduced as a result. Better reaction selectivity is achieved by feedingthe reactants into the reaction zone in molar ratios within the statedlimits and by keeping the molar ratios as constant as possible.

The reaction zone may be the interior of a stirred reactor or a sequenceof connected reactors. In general, the reaction parameters; such as (1)amounts of substance, (2) reaction temperature and (3) mean residencetime; can be matched to one another in such a way that the reactionproceeds isothermally and, at the same time, adiabatically. A reactorwith heating equipment (for long mean residence times and/or smallamounts of substance) and cooling equipment (for short mean residencetimes and/or large amounts of substance) is preferable, since it ensuresthe desired flexibility in controlling the reaction. However, while thereaction can have both cooling and heating capabilities, it is notnecessary to switch back and forth from one to the other, since thepresent process runs stably and continuously.

To minimize back-mixing of the 2-acetyl-γ-butyrolactone, initiallypresent as the alkali metal enolate, with the starting materials, thereaction zone can be subdivided by conducting the process in a reactorcascade. It is then possible to set different (generally increasing)temperatures in the various reactors. The present method can also beimplemented in a flow tube where laminar flow virtually rules out anyback-mixing. Here, too, a temperature gradient can be set if desired.

The optimum temperature and the optimum mean residence time in thereaction zone are interdependent. Preferably, the temperature is in therange of from 20° to 160° C., more preferably from 30° to 140° C. Themean residence time is preferably from 5 minutes to 30 hours, morepreferably from 10 minutes to 20 hours. For a given acetic acid ester, agiven condensation agent and a specific geometry of the reaction zone,the optimum parameters can readily be determined by preliminary trials.

The reaction mixture which leaves the reaction zone, containing2-acetyl-γ-butyrolactone in the form of its enolate, generally has asufficiently low viscosity at about 50° C. to be conveyable bymechanical pumps. In the case of lower temperatures and/or an onlyslight excess of acetic acid ester, an inert solvent such as toluene canbe added to make the reaction mixture pumpable. The reaction mixture canbe drawn off batchwise or, preferably, continuously from the reactionzone.

The reaction mixture is then protonated with an inorganic acid, anorganic acid or an organic acid anhydride. Suitable inorganic acidsinclude hydrohalic acids (such as hydrochloric acid), sulfuric acid,phosphoric acid, nitric acid and carbonic acid (as carbon dioxide).Suitable organic acids include carboxylic acids such as formic acid,acetic acid and propionic acid, and aliphatic or aromatic sulfonic acidssuch as benzene- or p-toluenesulfonic acid.

A suitable organic acid anhydride is, for example, acetic anhydride. Aparticularly preferred acid is sulfuric acid. The acids are preferablyused with a certain percentage of water, e.g. from about 10 to 70 wt. %,so that complete protonation, without excess acid, is achieved andmonitored by pH measurement. If carbonic acid or organic acid anhydrideis used as the protonating agent, an appropriate amount of water shouldbe supplied in some other way.

The protonation is preferably carried out by metering both the acid andthe reaction mixture simultaneously into a protonation zone (orneutralization zone). In the process, a uniform pH is establishedvirtually immediately in the mixture formed. The pH can, by means ofconventional instrumentation and control engineering, preferably withthe aid of the acid infeed as a controlled variable, be kept constant ina range which is preferably from 4 to 7, more preferably from 5 to 6.5.In the course of the protonation (or neutralization), heat is released,so that it is necessary to maintain the temperatures of the reactionmixture in the range of from -5° to +50° C., preferably from 10° to 30°C., by cooling.

To start up the plant or apparatus, acetic acid ester or an inertsolvent is preferably introduced as an initial charge, after whichacetic acid ester and γ-butyrolactone, separately or mixed together, andthe condensation agent, as a powder or as a suspension, are fed in inthe correct proportions. After some time, removal of the reactionmixture is started while, at the same time, the reactants continue to beadded in the desired proportions. The amounts fed in and drawn off arecontrolled to ensure that the level of the liquid phase in the reactoror reactors is maintained.

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

EXAMPLES Example 1

Into a 2 l glass reactor equipped with a solids feeder, 500 ml of ethylacetate were introduced as an initial charge and heated to 55° C. Then,over a period of 60 minutes, 259 g of sodium methoxide powder weremetered in via the solids feeder and, at the same time, a mixture of 344g of γ-butyrolactone and 529 g of ethyl acetate was metered in using ametering pump. The reactor contents were kept at 55° C. by slightheating and were thoroughly mixed with the aid of a propeller mixer. Thereaction mixture began to be drawn off at a rate of 1132 g/h using afurther metering pump, while at the same time the infeed of 259 g/h ofsodium methoxide powder and of 344 g/h of γ-butyrolactone and of 529 g/hof ethyl acetate (the latter in a mixture) continued in order to keepthe liquid level in the reactor constant. The mean residence time in thereactor was about 60 minutes. After a few hours of this continuous modea steady state was established. The conversion of the γ-butyrolactonewas approximately 85%, according to GC analysis, and the selectivity ofthe formation of 2-acetyl-γ-butyrolactone was approximately 80%, basedon γ-butyrolactone used.

The reaction mixture (1132 g/h) drawn off from the glass reactor wasconveyed into a pressure-proof heatable flow tube as a second reactor,within which a temperature of 90° C. is maintained by heating. Due tothe vapor pressure of the low-boiling components of the reactionmixture, an internal pressure of approximately 0.6 Mpa was establishedin the process. The mean residence time of the mixture in the pressurereactor was approximately 2 hours. An amount of the mixturecorresponding to the reaction mixture fed in hourly was drawn off hourlyas offtake.

The mixture drawn off from the pressure reactor (1132 g/h) and 296 g of80% strength sulfuric acid were metered into a protonation reactor (orneutralization reactor) equipped with a propeller mixer, to establish apH value of 6±0.2. The amount of the mixture in the protonation reactorwas controlled in such a way that the mean residence time wasapproximately 4 hours. About 1430 g of protonation mixture were drawnoff hourly, and sodium sulfate was suspended therein. This was removedby filtration and washed with a small amount of methanol. The filtratewas combined with the wash liquid and distilled, with the low-boilingcomponents first being removed in a rotary evaporator. Distillation overa 20 cm column packed with Raschig rings gave 466 g/h ofγ-acetylbutyrolactone which, according to GC analysis, had a purityof >99%. The yield was 91% of the theoretical yield, based onγ-butyrolactone used.

Example 2

Into a 2 l glass reactor equipped with a solids feeder and an agitator,500 ml of methyl acetate were introduced as an initial charge and heatedto 45° C. Then, over a period of 1 hour, 194 g of sodium methoxidepowder were metered in via the solids feeder and, at the same time, apreviously prepared mixture of 258 g of γ-butyrolactone and 422 g ofmethyl acetate was metered in by means of a metering pump. Initially,the reactor contents were kept at 45° C. by cooling. After about anhour, removal of the reaction mixture began, at a rate of 874 g/h, withthe aid of a further metering pump, while at the same time the infeed of194 g/h of sodium methoxide powder, 258 g/h of γ-butyrolactone and 422g/h of methyl acetate (the latter two being mixed) continued in order tomaintain a constant liquid level in the reactor and give a residencetime of about 1 h. After the removal of the reaction mixture had begun,the temperature of the reactor contents was kept at 45° C. by slightheating.

With the aid of the abovementioned second metering pump, the reactionmixture drawn from the reactor was conveyed continuously to a secondsteel pressure reactor which had a volume of 4 l and was equipped with apropeller mixer. This steel pressure reactor was heated to an internaltemperature of 100° C., and an internal pressure of 0.6 Mpa wasestablished. This reactor was fed hourly with 874 g of reaction mixture,and the same amount of reaction mixture was drawn off.

The reaction mixture drawn off was protonated as described in Example 1,with the appropriate quantities of sulfuric acid. After removal of thesodium sulfate by filtration and washing with methanol, the filtrate andwash methanol were combined and distilled. Advantageously, thelow-boiling components were first removed with the aid of a rotaryevaporator or a thin-film evaporator. Distillation of the residue over a20 cm column packed with Raschig rings gave 332 g/h of2-acetyl-γ-butyrolactone (99% purity according to GC), which correspondsto a yield of 86% of the theoretical yield, based on γ-butyrolactoneused.

Example 3

Into the 2 l glass reactor of the previous examples, 500 ml of toluenewere introduced as initial charge and heated to 60° C. Over a period of60 min, a mixture of 258 g of γ-butyrolactone and 502 g of ethyl acetatewas then fed in via the metering pump, and a suspension of 244 g ofsodium methoxide powder in 200 g of toluene was fed in via a laboratorygear pump. The suspension of sodium methoxide powder in toluene wasthoroughly mixed in a separate receiver. Initially, the reactor wascooled, to maintain an internal temperature of the reactor of 60° C.After 1 h removal of the reaction mixture began, while the infeed of 258g/h of γ-butyrolactone mixed with 502 g of ethyl acetate and of 244 g/hof sodium methoxide powder suspended in 200 g/h of toluene wascontinued. The mean residence time was approximately 1 h. The mixturedrawn from the reactor was transferred into the second steel pressurecylinder described in Example 2, whose internal temperature was again100° C., and the internal pressure was again 0.6 MPa.

The reaction mixture (1204 g/h) leaving the steel pressure cylinder wasprotonated in the manner described in Example 1. The sodium sulfate wasfiltered off and washed with methanol, the low-boiling components arefirst removed in a rotary evaporator, and by distillation of the residueover the 20 cm column packed with Raschig rings, 338 g of2-acetyl-γ-butyrolactone (99% purity according to GC), corresponding toa yield of 88% of the theoretical yield, based on γ-butyrolactone used,were obtained.

Example 4

The same procedure was followed as in Example 1, except that theprotonation was carried out with 50% strength phosphoric acid.Distillation gave 464 g/h of 2-acetyl-γ-butyrolactone (98.5% purityaccording to GC), corresponding to a yield of 91% of the theoreticalyield, based on γ-butyrolactone used.

Example 5

The same procedure was followed as in Example 1, except that theprotonation was carried out with 60% strength acetic acid. Distillationgave 458 g/h of 2-acetyl-γ-butyrolactone (98.5% purity according to GC),corresponding to a yield of 88% of the theoretical yield, based onγ-butyrolactone used.

This application is based on German Patent Application 196 06 975.0,filed with the German Patent Office on Feb. 24, 1996, the entirecontents of which are hereby incorporated by reference.

Obviously, additional modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed as new and is desired to be secured by Letters Patent ofthe United States is:
 1. A method for preparing2-acetyl-γ-butyrolactone, comprising:continuously feedingγ-butyrolactone, an acetic acid ester and a condensation agent to areaction zone in a ratio of from 1.0 to 6.0 parts by mols of acetic acidester and from 0.9 to 1.6 parts by mols of the condensation agent perpart by mols of γ-butyrolactone; condensing γ-butyrolactone with theacetic acid ester in the reaction zone in the presence of thecondensation agent to form a reaction mixture comprising a2-acetyl-γ-butyrolactone enolate; withdrawing the reaction mixture fromthe reaction zone; and protonating the 2-acetyl-γ-butyrolactone enolate.2. The method as claimed in claim 1, wherein said withdrawing step isperformed batchwise.
 3. The method as claimed in claim 1, wherein saidwithdrawing step is performed continuously.
 4. The method as claimed inclaim 1, wherein the condensing step is performed at a temperature inthe reaction zone of from 20° to 160° C.
 5. The method as claimed inclaim 4, wherein the temperature in the reaction zone is from 30° to140° C.
 6. The method as claimed in claim 1, wherein the condensing stepis performed with a mean residence time in the reaction zone of from 5minutes to 30 hours.
 7. The method as claimed in claim 6, wherein themean residence time in the reaction zone is from 10 minutes to 20 hours.8. The method as claimed in claim 1, wherein the condensing step isperformed in a reactor cascade having a plurality of reactor zones. 9.The method as claimed in claim 1, wherein the acetic acid ester is anester prepared by condensation of acetic acid with an alkanol havingfrom 1 to 4 carbon atoms.
 10. The method as claimed in claim 1, whereinthe acetic acid ester is methyl acetate.
 11. The method as claimed inclaim 1, wherein the condensation agent is an alkali metal alcoholate ofan alkanol having from 1 to 4 carbon atoms.
 12. The method as claimed inclaim 1, wherein the condensation agent is sodium methoxide.
 13. Themethod as claimed in claim 11, wherein the condensation agent is fedinto the reaction zone in a finely disperse form.
 14. The method asclaimed in claim 13, wherein the condensation agent is fed into thereaction zone in a finely disperse form suspended in an aliquot of theacetic acid ester or an inert, nonpolar solvent.
 15. The method asclaimed in claim 12, wherein the condensation agent is fed into thereaction zone in a finely disperse form.
 16. The method as claimed inclaim 15, wherein the condensation agent is fed into the reaction zonein a finely disperse form suspended in an aliquot of the acetic acidester or an inert, nonpolar solvent.
 17. The method as claimed in claim1, wherein the protonating step is performed continuously with aninorganic acid, an organic acid or an organic acid anhydride and at atemperature of from -5° to +50° C. and a pH of from 4 to
 7. 18. Themethod as claimed in claim 1, wherein the protonating step is performedcontinuously with sulfuric acid at a temperature of from 10° to 30° C.and a pH of from 5 to 6.